Abstract Stress is a major factor contributing to development of psychiatric disorders, including schizophrenia. Previous studies have revealed possible abnormalities in the hypothalamic- pituitary-adrenal (HPA) axis in schizophrenia, with evidence that schizophrenia patients show abnormal levels of cortisol, the main stress hormone, in response to stress . Cortisol primes the body to respond to stress, but also suppresses inflammatory activity that could be detrimental to health. There is increasing evidence that schizophrenia is characterized by a state of low-grade inflammation, though the origin and consequences of this inflammation are unknown. Both cortisol and inflammatory markers may have effects on the brain, and conversely, the brain may exert top-down control over cortisol and immune responses to stress. This K23 mentored clinical research project, submitted by Principal Investigator Dr. Joshua Chiappelli, will compare individuals with schizophrenia to healthy controls in how they respond to laboratory based stressful challenges, including a psychological stressor and a somatic stressor that involves exposure to pain. Levels of cortisol and IL-6 will be measured in saliva samples collected before and after these stress challenges to examine if schizophrenia patients have an abnormality in the normal suppression of inflammation by cortisol. Levels of glutamate in the brain will be examined with magnetic resonance spectroscopy (MRS) concurrently with cortisol and IL-6 to test if peripheral responses to stress are modulated by the brain. This project will take place at the Maryland Psychiatric Research Center (MPRC), part of the University of Maryland School of Medicine. The MPRC operates several outpatient clinics specializing in care of schizophrenia patients as well as a MR imaging center; the research programs of the MPRC include preclinical and clinical research studies focusing on the causes, course, and treatment of schizophrenia. The K23 proposal also includes a comprehensive training plan to facilitate Dr. Chiappelli?s development into an independent clinical researcher. Mentorship will be provided by Dr. Elliot Hong, an expert in schizophrenia and neuroimaging; Dr. Laura Rowland, an expert in use of magnetic resonance spectroscopy in schizophrenia; Dr. Leonardo Tonelli, an expert on neuroimmunology; and Dr. Diana Fishbein, an expert on stress and development. This project will provide preliminary data for further R01 investigations into the mechanisms of stress pathophysiology in schizophrenia and will provide Dr. Chiappelli with the necessary education and skill development to lead further translational studies as an independent clinical investigator.